Continuous Enantioselective α-Alkylation of Ketones via Direct Photoexcitation.

Motivated by the scarcity of enantioselective direct intermolecular α-alkylation reactions of ketones with simple alkyl halides, we report a photo-organocatalytic process to access diethyl 2-(2-oxocyclohexyl)malonate and derivatives in good yield and enantioselectivity. The reaction design is based on highly abundant and nature-derived 9-amino-9-deoxy-epi-cinchona alkaloids to activate ketones as transient secondary enamines, which exist unfavorably in equilibrium with imines. These condensed species can serve as powerful photoinitiators via direct photoexcitation. This concept provides access to both enantiomeric antipodes. In addition to introducing an uncomplicated batch-optimized procedure, we investigated the feasibility and limitations of implementing the reaction in continuous flow, thus enabling to obtain diethyl 2-(2-oxocyclohexyl)malonate with a productivity of 47 µmol/h and 84% enantioselectivity.

Supported Ionic Liquid Phase (SILP) Allylic Alkylation of Amines in Continuous Flow.

We present the use of Pd-complex-containing supported ionic liquid phases (SILPs) as a novel approach for continuous-flow allylic alkylation of N-nucleophiles. This immobilization strategy gave simple access to air-tolerating catalyst frameworks, providing rapid and convenient access to various achiral and chiral N-allylation products. Under optimized conditions, the flow-reaction could be maintained for 3.5 hours with constant product output; meanwhile, only a marginal 0.7 wt % of ionic liquid leaching and no detectable palladium-complex leaching could be observed.

Photocatalyst-free hydroacylations of electron-poor alkenes and enones under visible-light irradiation.

Herein we present a photocatalyst- and additive-free radical hydroacylation of electron-poor double bonds under mild reaction conditions. Using 4-acyl-Hantzsch ester radical reservoirs, various Michael acceptors, enones and para-quinone methide substrates could be used. The protocol enabled further derivatizations and it could also be extended to a few unactivated alkenes. Moreover, the nature of the radical process was also investigated.

Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts.

Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.

Sterically Demanding Flexible Phosphoric Acids for Constructing Efficient and Multi-Purpose Asymmetric Organocatalysts.

Herein, we present a novel approach for various asymmetric transformations of cyclic enones. The combination of readily accessible chiral diamines and sterically demanding flexible phosphoric acids resulted in a simple and highly tunable catalyst framework. The careful optimization of the catalyst components led to the identification of a particularly powerful and multi-purpose organocatalyst, which was successfully applied for asymmetric epoxidations, aziridinations, aza-Michael-initiated cyclizations, as well as for a novel Robinson-like Michael-initiated ring closure/aldol cyclization. High catalytic activities and excellent stereocontrol was observed for all four reaction types, indicating the excellent versatility of our catalytic system. Furthermore, a simple change in the diamine's configuration provided easy access to both product antipodes in all cases.

Chiral Phosphoric Acids as Versatile Tools for Organocatalytic Asymmetric Transfer Hydrogenations.

Herein, recent developments in the field of organocatalytic asymmetric transfer hydrogenation (ATH) of C=N, C=O and C=C double bonds using chiral phosphoric acid catalysis are reviewed. This still rapidly growing area of asymmetric catalysis relies on metal-free catalysts in combination with biomimetic hydrogen sources. Chiral phosphoric acids have proven to be extremely versatile tools in this area, providing highly active and enantioselective alternatives for the asymmetric reduction of α,ß-unsaturated carbonyl compounds, imines and various heterocycles. Eventually, such transformations are more and more often used in multicomponent/cascade reactions, which undoubtedly shows their great synthetic potential and the bright future of organocatalytic asymmetric transfer hydrogenations.

Counterion-Enhanced Pd/Enamine Catalysis: Direct Asymmetric α-Allylation of Aldehydes with Allylic Alcohols by Chiral Amines and Achiral or Racemic Phosphoric Acids.

We report a straightforward and efficient Pd/enamine catalytic procedure for the direct asymmetric α-allylation of branched aldehydes. The use of simple chiral amines and easily prepared achiral or racemic phosphoric acids, together with a suitable Pd-source resulted in a highly active and enantioselective catalyst system for the allylation of various α-branched aldehydes with different allylic alcohols. The reported procedure could provide an easy access to both product antipodes. Furthermore, two possible orthogonal derivatizations of the enantioenriched aldehydes were performed without any decrease in enantioselectivity.

Counterion Enhanced Organocatalysis: A Novel Approach for the Asymmetric Transfer Hydrogenation of Enones.

We present a novel strategy for organocatalytic transfer hydrogenations relying on an ion-paired catalyst of natural l-amino acids as main source of chirality in combination with racemic, atropisomeric phosphoric acids as counteranion. The combination of a chiral cation with a structurally flexible anion resulted in a novel chiral framework for asymmetric transfer hydrogenations with enhanced selectivity through synergistic effects. The optimized catalytic system, in combination with a Hantzsch ester as hydrogen source for biomimetic transfer hydrogenation, enabled high enantioselectivity and excellent yields for a series of α,ß-unsaturated cyclohexenones under mild conditions. Moreover, owing to the use of readily available and chiral pool-derived building blocks, it could be prepared in a straightforward and significantly cheaper way compared to the current state of the art.

Enantiomerization of Axially Chiral Biphenyls: Polarizable MD Simulations in Water and Butylmethylether.

In this study, we investigate the influence of chiral and achiral cations on the enantiomerization of biphenylic anions in n-butylmethylether and water. In addition to the impact of the cations and solvent molecules on the free energy profile of rotation, we also explore if chirality transfer between a chiral cation and the biphenylic anion is possible, i.e., if pairing with a chiral cation can energetically favour one conformer of the anion via diastereomeric complex formation. The quantum-mechanical calculations are accompanied by polarizable MD simulations using umbrella sampling to study the impact of solvents of different polarity in more detail. We also discuss how accurate polarizable force fields for biphenylic anions can be constructed from quantum-mechanical reference data.

Simple lysis of bacterial cells for DNA-based diagnostics using hydrophilic ionic liquids.

The extraction of nucleic acids from microorganisms for subsequent molecular diagnostic applications is still a tedious and time-consuming procedure. We developed a method for the rapid preparation of genomic DNA from bacteria based on hydrophilic ionic liquids (ILs). First, we tested eight ILs in different buffer systems for their inhibitory effects on quantitative PCR. The cell lysis potential of different IL/buffer combinations was assessed by application on Enterococcus faecalis as a model organism for Gram-positive bacteria. The two best ILs, choline hexanoate and 1-ethyl-3-methylimidazolium acetate, were compared with the reference enzymatic method and two commercial DNA extraction kits. All methods were evaluated on four Gram-positive and four Gram-negative bacterial species that are highly relevant for environmental, food, or clinical diagnostics. In comparison to the reference method, extraction yields of the IL-based procedure were within one order of magnitude for most of the strains. The final protocol for DNA extraction using the two ILs is very low-cost, avoids the use of hazardous chemicals and can be performed in five minutes on a simple heating block. This makes the method ideal for high sample throughput and offers the opportunity for DNA extraction from bacteria in resource-limited settings or even in the field.

Synthesis of l-threitol-based crown ethers and their application as enantioselective phase transfer catalyst in Michael additions.

A few new l-threitol-based lariat ethers incorporating a monoaza-15-crown-5 unit were synthesized starting from diethyl l-tartrate. These macrocycles were used as phase transfer catalysts in asymmetric Michael addition reactions under mild conditions to afford the adducts in a few cases in good to excellent enantioselectivities. The addition of 2-nitropropane to trans-chalcone, and the reaction of diethyl acetamidomalonate with ß-nitrostyrene resulted in the chiral Michael adducts in good enantioselectivities (90% and 95%, respectively). The substituents of chalcone had a significant impact on the yield and enantioselectivity in the reaction of diethyl acetoxymalonate. The highest enantiomeric excess (ee) values (99% ee) were measured in the case of 4-chloro- and 4-methoxychalcone. The phase transfer catalyzed cyclopropanation reaction of chalcone and benzylidene-malononitriles using diethyl bromomalonate as the nucleophile (MIRC reaction) was also developed. The corresponding chiral cyclopropane diesters were obtained in moderate to good (up to 99%) enantioselectivities in the presence of the threitol-based crown ethers.

Novel Alternating Current Electrospinning of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) Nanofibers for Dissolution Enhancement: The Importance of Solution Conductivity.

Novel, high-yield alternating current electrospinning (ACES) and direct current electrospinning methods were investigated to prepare high-quality hydroxypropylmethylcellulose acetate succinate (HPMCAS) fibers for the dissolution enhancement of poorly soluble spironolactone. Although HPMCAS is of great pharmaceutical importance as a carrier of marketed solid dispersion-based products, it was found to be unprocessable using electrospinning. Addition of small amounts of polyethylene oxide as aid polymer provided smooth fibers with direct current electrospinning but strongly beaded products with ACES. Solution characteristics were thus modified by introducing further excipients. In the presence of sodium dodecyl sulfate, high-quality, HPMCAS-based fibers were obtained even at higher throughput rates of ACES owing to the change in conductivity (rather than surface tension). Replacement of sodium dodecyl sulfate with non-surface-active salts (calcium chloride and ammonium acetate) maintained the fine quality of nanofibers, confirming the importance of conductivity in ACES process. The HPMCAS-based fibers contained spironolactone in an amorphous form according to differential scanning calorimetry and X-ray powder diffraction. In vitro dissolution tests revealed fast drug release rates depending on the salt used to adjust conductivity. The presented results signify that ACES can be a prospective process for high-scale production of fibrous solid dispersions in which conductivity of solution has a fundamental role.